This study found that hyperemic blood flow after exercise during partial cuff restriction was reduced in CFS patients compared to controls. Blood flow was measured as the integrated flow over the first 60 seconds of recovery, and took into account lean leg mass with no group differences in blood pressure. We also found that recovery of oxygen saturation was reduced in CFS patients after exercise, consistent with our previous studies(23
). CFS patients have been reported to have altered sympathetic activity and impaired autonomic tone(7
). The measurements of integrated flow and oxygen delivery might reflect autonomic impairment. While there are no available studies on CFS to compare our blood flow measurements, previous studies have suggested that CFS patients have cholinergic abnormalities in peripheral microcirculation (19
). Patients with fibromyalgia, a related syndrome, have reported reduced blood flow (3
) and reduced capillary densities (20
) relative to control subjects.
The peak blood flow response for the no cuff exercise conditions was not reduced in the CFS patients compared to controls, in contrast to the integrated flow responses. The lack of a difference in peak blood flow responses following exercise was similar to our most recent study which found no differences in peak blood flow after cuff ischemia (25
). It is not clear why we would obtain different conclusions for peak and integrated blood flow. One possibility is that integrated flow values might be more sensitive markers of flow abnormalities in CFS patients than peak flow. We have found altered rates of recovery of blood flow after ischemia in both older and spinal cord injured subjects(27
), consistent with altered autonomic tone in these groups(9
). These results suggest that the capacity for peak blood flow was not reduced in CFS patients compared to controls, but that the actual delivery of oxygen might be reduced due to alterations in the integrated flow response.
The question that comes from our results is what is the importance of the reduced integrated flow and oxygen delivery responses? Our primary hypothesis was that restricting blood flow during recovery would impair oxidative metabolism in CFS patients to a greater extent that control subjects. We found no evidence that this was true. Oxidative capacity measured with 31P MRS during recovery from exercise with partial cuff occlusion was not impaired in CFS subjects. We did see a graded decrease in blood flow and oxidative metabolism with increasing cuff pressure, suggesting that partial cuff inflation did restrict blood flow and did reduce oxidative metabolism. As shown in , we took care to design the experiment to minimize residual levels of muscle oxygen prior to the partial cuff occlusion. This included applying the cuff prior to exercise to assist in reducing stored oxygen levels in the muscles, and keeping the cuff on the muscle for approximately 10 seconds after cessation of exercise to assure that PCr recovery was stopped. So while flow restriction did reduce oxidative metabolism, there was no evidence that CFS patients were more sensitive to flow restriction than control subjects.
A number of previous studies have examined the effects of flow restriction on muscle metabolism and function. Conrad and Green (6
) found that cuff pressures of 50-60 mmHg reduced direct measures of resting arterial flow by 5-9% in a cat hindlimb preparation. In a study on humans, Hiatt et al. (15
) found much larger changes with cuff pressures of 50 mmHg, including 44% decreases in femoral artery diameter directly under the cuff and a 38% decrease in blood velocity down stream of the cuff. These measurements were made under stable conditions and it is not clear how they compare to our measurements, as we were primarily concerned with changes in blood flow during the first minute after partial cuff occlusion. Sundberg et al.(37
) found that lower body negative pressures of 50 mmHg reduced arterial blood flow by 16% during exercise, and also resulted in lower venous oxygen saturation and higher venous lactate levels during exercise. Cole and Brown used cuff occlusion during electrical stimulation, and found that cuff pressures of 50 and 80 mmHg resulted in force reductions of 15-22 % (4
). Iwanaga, et al. (17
) found cuff occlusion at systolic and diastolic blood pressures to have pressure dependent effects on work rate, phosphocreatine levels, and intracellular pH during exercise. Taken together, these studies support our findings that even relatively low occlusion pressures can restrict blood flow and impair muscle metabolism.
One of the complications of our approach is that partial arterial occlusion is also associated with venous occlusion. This dramatically altered the arterial velocity waveform (), most likely due to back pressure associated with the accumulation of blood in the venous system. The accumulation of blood also influenced the PCr measurements as we could detect changes in PCr concentration in association with the change in cuff pressure (). Partial cuff ischemia reduced PCr values and altered the shape of the PCr recovery curves. We chose to correct our PCr values using a linear increase in blood volume during the time period that the partial cuff pressure was applied. We based this in part on the NIRS results which showed that partial cuff ischemia increased blood volume. Interestingly, the increase in blood volume appeared to be primarily deoxygenated blood as the level of oxygen saturation was progressively reduced during partial cuff ischemia. These results suggest that alterations in blood volume need to be taken into account when evaluating the vascular response to partial cuff ischemia.
Another limitation of our study was the measurement of peak blood flow using two cardiac cycles. While the short measurement time interval allowed us to track the rapidly changing blood flows needed to measure a peak flow value, it does introduce some added variability. For example, we did not control for the effects of respiration on time averaged blood flow. We did use integrated flow over 60 seconds when comparing blood flow during partial cuff ischemia to PCr recovery rates. We felt that blood flow over 60 seconds would more accurately reflect oxygen delivery while PCr was being resynthesized. This would also reduce variability of the measurements due to respiration and other transient effects.
Other approaches have been used to evaluate muscle metabolism in response to altered oxygen delivery. Studies by Hogan et al.(16
) showed that PCr levels during exercise were sensitive to the concentration of oxygen during exercise. The rate of PCr resynthesis was also altered by altering oxygen concentrations in inspired air, but only in well-trained subjects(32
). It is hard to compare the magnitude of reduction in oxygen delivery in the studies that altered the concentrations of inspired oxygen to our study where we reduced blood flow. However, their results are consistent with ours and support the idea that oxidative metabolism is linked to oxygen delivery during exercise.
Oxidative metabolism, as measured by the rate of PCr recovery after exercise was not different between the CFS patients and our controls in this study. This was reported in an earlier manuscript (25
). In addition, CFS patients showed the same degree of reduction of oxidative metabolism as control subjects with partial cuff occlusion to reduced blood flow. The lack of impairment of oxidative metabolism in CFS patients was consistent some previous studies(18
), but not others(23
). It is not clear why the different studies have different conclusions, especially our current study and our previous study, which evaluated CFS and controls subjects from the same source and using basically the same equipment and protocols. Most of the subjects in our study reported `severe' CFS symptoms, so we feel that altered muscle metabolism is not a requirement for CFS symptoms to be present. It is possible that our lack of change in blood flow responses was due to the lack of metabolic differences, and that CFS patients with clearly abnormal oxidative metabolism would have abnormal blood flow.
In summary, CFS patients had rates of oxidative metabolism that were not different from control subjects, even with partial restriction of blood flow. This suggests that the CFS symptoms that these patients reported were not caused by peripheral abnormalities in oxidative metabolism. However, we did find evidence that CFS patients had reduced oxygen delivery, based both on NIRS measurements of the rate of recovery after exercise, and reductions in the integrated flow response to partial arterial occlusion. These measurements do support the hypothesis that CFS patients have abnormal control of circulation, perhaps due to altered sympathetic and or parasympathetic tone. However, it is not clear how significant the changes in control of circulation are as they were not associated with changes in muscle oxidative metabolism, which is normally highly sensitive to oxygen delivery. Partial cuff occlusion resulted in graded reductions in oxidative metabolism, even with occlusion pressure below diastolic pressure. This suggests that partial occlusion of blood flow could be a useful method of evaluating oxygen delivery and muscle metabolism as long as the effects of venous filling are taken into account.